Currently, 30% of adults in the U.S. are obese, with the prevalence of obesity rising each year (CDC BRFSS, 2012). Obesity contributes to type 2 diabetes, cardiovascular disease, and many cancers, but is very hard to treat clinically. In 2011, the NIH released its new strategic plan for NIH obesity research to provide a blueprint that will encourage the research community to examine the epidemic of obesity from diverse perspectives...in order to develop and evaluate new prevention and treatment strategies. The proposed work directly addresses this need by using novel approaches to understand the neurobehavioral mechanisms that promote obesity. In people, exposure to cues associated with food (food-cues), like the smell of brownies or a blinking donuts sign, increases food craving and the amount of food consumed (Fedoroff et al. 1997, Soussignan et al. 2012). Obese people report stronger food craving and eat larger portions in response to food-cues. Further, increases in activity of the nucleus accumbens (NAc) triggered by food-cues predict future weight gain in normal weight people and future inability to lose weight after obesity (Murdaugh et al. 2011; Demos et al. 2012). Thus in people, enhanced neurobehavioral responses to food-cues contribute to obesity. But, the mechanism underlying this enhanced neurobehavioral reactivity in obese and obesity-susceptible individuals is unknown. Our long-term goal is to understand the neurobiological mechanisms underlying enhanced cue- triggered 'craving' in obesity-susceptible and obese individuals. AMPA type glutamate receptors (AMPAR) provide the main source of excitation to the NAc. The NAc plays a critical role in food-cue triggered motivation in non-obese rats (Cardinal et al. 2002; Kelley, 2004; Everitt & Robbins, 2005). Disruption of AMPAR synaptic trafficking blocks the expression of cue-triggered motivation for sucrose in non-obese mice (Crombag et al. 2008a,b). These data suggest that enhancement of AMPAR function in the NAc may contribute to enhanced food-cue triggered motivation in obesity. However, no studies have examined NAc glutamate transmission or mechanisms of food-cue motivation in any rodent model of obesity. Our preliminary data show that obesity- prone are more motivated by food-cues and have increased NAc surface levels of AMPARs compared to obesity-resistant. We will combine rodent models of obesity with behavioral, electrophysiological and biochemical measures to determine the contribution of obesity, diet, and NAc glutamate transmission to enhanced motivation for food-cues. This work will have significant translational relevance given that modulation of glutamate transmission is a viable therapeutic approach in other disease models (Sidorov et al., 2013; Kreitzer and Malenka 2007; Loweth et al., 2013; Schwendt et al., 2012). Modulation of glutamate transmission will help those struggling with obesity to maintain a healthy weight by dampening the ability of food-cues to influence their behavior. We strongly believe this work will open new avenues for treatment by providing a better understanding of the behavioral and neural differences underlying enhanced motivation triggered by food-cues in obesity.